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1.
Br J Surg ; 102(12): 1561-6, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26206386

RESUMEN

BACKGROUND: Several risk factors for complications after pancreaticoduodenectomy have been reported. However, the impact of intraoperative bacterial contamination on surgical outcome after pancreaticoduodenectomy has not been examined in depth. METHODS: This retrospective study included patients who underwent pancreaticoduodenectomy and peritoneal lavage using 7000 ml saline between July 2012 and May 2014. The lavage fluid was subjected to bacterial culture examination. The influence of a positive bacterial culture on surgical-site infection (SSI) and postoperative course was evaluated. Risk factors for positive bacterial cultures were also evaluated. RESULTS: Forty-six (21.1 per cent) of 218 enrolled patients had a positive bacterial culture of the lavage fluid. Incisional SSI developed in 26 (57 per cent) of these 46 patients and in 13 (7.6 per cent) of 172 patients with a negative lavage culture (P < 0.001). Organ/space SSI developed in 32 patients with a positive lavage culture (70 per cent) and in 43 of those with a negative culture (25.0 per cent) (P < 0.001). Grade B/C pancreatic fistula was observed in 22 (48 per cent) and 48 (27.9 per cent) respectively of patients with positive and negative lavage cultures (P = 0.010). Postoperative hospital stay was longer in patients with a positive lavage culture (28 days versus 21 days in patients with a negative culture; P = 0.028). Multivariable analysis revealed that internal biliary drainage, combined colectomy and a longer duration of surgery were significant risk factors for positive bacterial culture of the lavage fluid. CONCLUSION: Intraoperative bacterial contamination has an adverse impact on the development of SSI and grade B/C pancreatic fistula following pancreaticoduodenectomy.


Asunto(s)
Cavidad Abdominal/microbiología , Bacterias/aislamiento & purificación , Enfermedades Pancreáticas/cirugía , Pancreaticoduodenectomía/efectos adversos , Lavado Peritoneal/métodos , Infección de la Herida Quirúrgica/microbiología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Incidencia , Japón/epidemiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Infección de la Herida Quirúrgica/epidemiología , Infección de la Herida Quirúrgica/terapia , Tasa de Supervivencia/tendencias
2.
J Hosp Infect ; 96(1): 29-34, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28377180

RESUMEN

BACKGROUND: Analysis of bloodstream infections (BSIs) is valuable for their diagnosis, treatment and prevention. However, limited data are available in Japan. AIM: To investigate the characteristics of patients with bacteraemia in Japan. METHODS: This study was conducted in five hospitals from October 2012 to September 2013. Clinical, demographic, microbiological and outcome data for all blood-culture-positive cases were analysed. FINDINGS: In total, 3206 cases of BSI were analysed: 551 community-onset healthcare-associated (CHA)-BSIs, 1891 hospital-acquired (HA)-BSIs and 764 community-acquired (CA)-BSIs. The seven- and 30-day mortality rates were higher in patients with CHA- and HA-BSIs than in patients with CA-BSIs. The odds ratios (ORs) for seven-day mortality were 2.56 [95% confidence interval (CI) 1.48-4.41] and 2.63 (95% CI 1.64-4.19) for CHA- and HA-BSIs, respectively. The ORs for 30-day mortality were 2.41 (95% CI 1.63-3.57) and 3.31 (95% CI 2.39-4.59) for CHA- and HA-BSIs, respectively. There were 499 cases (15.2%) of central-line-associated BSI and 163 cases (5.0%) of peripheral-line-associated BSI. Major pathogens included coagulase-negative staphylococci (N = 736, 23.0%), Escherichia coli (N = 581, 18.1%), Staphylococcus aureus (N = 294, 9.2%) and Klebsiella pneumoniae (N = 263, 8.2%). E. coli exhibited a higher 30-day mortality rate among patients with HA-BSIs (22.3%) compared with patients with CHA-BSIs (12.3%) and CA-BSIs (3.4%). K. pneumoniae exhibited higher 30-day mortality rates in patients with HA-BSIs (22.0%) and CHA-BSIs (22.7%) compared with patients with CA-BSIs (7.8%). CONCLUSION: CHA- and HA-BSIs had higher mortality rates than CA-BSIs. The prognoses of E. coli- and K. pneumonia-related BSIs differed according to the category of bacteraemia.


Asunto(s)
Bacteriemia/epidemiología , Patógenos Transmitidos por la Sangre/aislamiento & purificación , Infecciones Relacionadas con Catéteres/microbiología , Infecciones Comunitarias Adquiridas/epidemiología , Infecciones Comunitarias Adquiridas/microbiología , Infección Hospitalaria/epidemiología , Anciano , Anciano de 80 o más Años , Bacteriemia/microbiología , Bacteriemia/mortalidad , Patógenos Transmitidos por la Sangre/efectos de los fármacos , Infecciones Relacionadas con Catéteres/epidemiología , Infecciones Relacionadas con Catéteres/mortalidad , Infecciones Comunitarias Adquiridas/mortalidad , Infección Hospitalaria/mortalidad , Escherichia coli/aislamiento & purificación , Femenino , Humanos , Japón/epidemiología , Klebsiella pneumoniae/aislamiento & purificación , Masculino , Persona de Mediana Edad , Mortalidad , Evaluación de Resultado en la Atención de Salud , Estudios Prospectivos , Staphylococcus aureus/aislamiento & purificación
3.
Cancer Res ; 42(3): 824-9, 1982 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-7059980

RESUMEN

The present study was designed to determine whether alterations in host metabolism associated with progressive tumor growth were a result of the anorexia frequently observed with cancer or could be attributed to other direct tumor effects. Rates of tyrosine flux, oxidation, and incorporation into protein, as well as fractional protein-synthetic rates in nonsecretory liver, muscle, and tumor, were determined in overnight-fasted rats, 5 to 6 (Stage I), 10 to 11 (Stage II), and 15 to 16 (Stage III) days following s.c. implantation of RNC-254 fibrosarcoma. Tumor-bearing rats were allowed to consume a purified diet containing 20% protein ad libitum, and results were compared to non-tumor-bearing rats pair fed quantities of food equivalent to tumor-bearing animals or allowed to consume the diet ad libitum. Results demonstrate that during later stages of tumor growth (Stage III) calorie intake and nontumor body weight gain were reduced in tumor-bearing rats (p less than 0.05). Fifteen and 16 days following implantation, there were significant changes in amino acid kinetics that were not observed after earlier periods of tumor growth and that could not be explained by any reduction in dietary intake. Rates of tyrosine appearance in the plasma and subsequent incorporation into whole-body protein were increased 33 and 34%, respectively (p less than 0.05), when compared to non-tumor-bearing rats fed equivalent quantities of food. Whole-body tyrosine oxidation rates were unchanged. Skeletal protein synthesis, as reflected by gastrocnemius or rectus abdominus muscle, was reduced from 10.5 and 10.1%/day to 7.4 and 6.0%/day, respectively (p less than 0.05), in tumor-bearing compared to pair-fed animals. The findings suggest that significant alterations in protein metabolism occur in advanced stages of experimental neoplastic disease which cannot be explained by reductions in dietary intake and are aimed at providing adequate quantities of endogenous amino acids for net tumor growth.


Asunto(s)
Músculos/metabolismo , Neoplasias/metabolismo , Proteínas/metabolismo , Tirosina/metabolismo , Animales , Peso Corporal , Caquexia/etiología , Proteínas en la Dieta , Ingestión de Energía , Femenino , Hígado/metabolismo , Estadificación de Neoplasias , Neoplasias/complicaciones , Neoplasias/patología , Biosíntesis de Proteínas , Ratas , Ratas Endogámicas , Factores de Tiempo
4.
Mech Ageing Dev ; 81(2-3): 97-106, 1995 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-8569284

RESUMEN

We investigated the difference in natural resistance to Legionella pneumophila infection between aged (18-20-month-old) and young (3-month-old) mice of ddY strain. Aged mice were more susceptible to the bacterial infection than young mice; 50% lethal doses of L. pneumophila for aged and young mice were 2.2 x 10(7) and 8.5 x 10(7) colony forming units (CFU), respectively, after intraperitoneal injection of the bacteria. The bacterial burden in the livers was larger in aged than young mice after a challenge with a sublethal dose of L. pneumophila. However, peritoneal macrophages of aged mice paradoxically had a greater capacity to kill intracellular L. pneumophila than those of young mice. Interferon-gamma (IFN-gamma) production from naive spleen cells was compared after an in vitro stimulation with formalin-killed L. pneumophila. Spleen cells of aged mice produced significantly less IFN-gamma than those of young mice. When anti-murine IFN-gamma monoclonal antibody was administered before the bacterial infection, the subsequent bacterial burden in the livers significantly increased in young but not in aged mice. These data suggest that, in aged mice, IFN-gamma production is depressed at an early phase of L. pneumophila infection and it renders aged mice more susceptible to the infection.


Asunto(s)
Envejecimiento/metabolismo , Interferón gamma/biosíntesis , Legionella pneumophila/crecimiento & desarrollo , Enfermedad de los Legionarios/metabolismo , Envejecimiento/inmunología , Animales , Anticuerpos Monoclonales , Susceptibilidad a Enfermedades , Femenino , Técnicas In Vitro , Interferón gamma/inmunología , Enfermedad de los Legionarios/inmunología , Hígado/microbiología , Macrófagos Peritoneales/inmunología , Ratones , Ratones Endogámicos
5.
Transplantation ; 70(5): 774-9, 2000 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-11003356

RESUMEN

BACKGROUND: Posttransplantation osteopenia leading to osteoporosis induced commonly by treatment with immunosuppressants including cyclosporine (CsA) is a severe complication and results in lowering the quality of life in patients receiving organ transplantation. FK506 is a newly developed immunosuppressant and is currently being used for the prevention of rejection after organ transplantation. In this study, to investigate whether FK506 as well as CsA would cause osteopenia or not, we evaluated the effect of FK506 on bone mineral density and several parameters relevant to bone metabolism in comparison with that of CsA using normal rats. METHODS: Ten-week-old male Sprague-Dawley rats were treated with FK506 (vehicle, 1 mg/kg, and 3.2 mg/kg) or CsA (vehicle, 10 mg/kg, and 32 mg/kg) by daily oral gavage for 28 days. Bone mineral density of the femur, plasma insulin-like growth factor I (IGF-I), and urinary deoxypyridinoline were determined by peripheral quantitative computerized tomography, radioimmunoassay, and enzyme-linked immunosorbent assay, respectively. RESULTS: The reduction in bone mineral density of the femur was observed in both FK506- and CsA-treated rats. The reduction in CsA-treated rats, however, was statistically significant and strikingly severe, whereas that in FK506-treated rats was much less severe than CsA. Plasma IGF-I levels were significantly elevated in FK506-treated rats but not in CsAtreated rats. Urinary deoxypyridinoline levels were unchanged in FK506-treated rats but elevated in CsA-treated rats. CONCLUSIONS: Compared with CsA, FK506 does not appear to induce severe osteopenia by high-turnover bone metabolism in the rat by mediating via IGF-I induction in part. The results suggest that FK506 may exert favorable effects on bone metabolism in patients with organ transplantation compared with CsA. To assess this idea, further clinical investigations focused on bone metabolism will be required.


Asunto(s)
Densidad Ósea/efectos de los fármacos , Ciclosporina/farmacología , Inmunosupresores/farmacología , Tacrolimus/farmacología , Aminoácidos/orina , Animales , Ácidos y Sales Biliares/sangre , Bilirrubina/sangre , Biomarcadores/orina , Peso Corporal , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/farmacología , Masculino , Ratas , Ratas Sprague-Dawley
6.
Am J Med Genet ; 31(3): 623-9, 1988 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-3067578

RESUMEN

We report on two Japanese sisters with Perrault syndrome, i.e., autosomal recessive ovarian dysgenesis associated with sensorineural deafness. They also had ataxic gait, pes equinovarus, nystagmus, limited extraocular movements, and short stature. One older affected sister had partial growth hormone deficiency. Our review included 21 patients from 8 families, including our patients; 16 are women with ovarian dysgenesis and deafness, 3 deaf males without gonadal defect, one a woman with ovarian dysgenesis without deafness, and one a girl with deafness in whom ovarian function was not evaluated. Perrault syndrome may not be uncommon; some cases may have gone unrecognized, especially when a single child in a family is affected.


Asunto(s)
Sordera/genética , Genes Recesivos , Disgenesia Gonadal/genética , Ovario/anomalías , Adolescente , Adulto , Preescolar , Femenino , Humanos , Masculino , Síndrome
7.
J Dermatol Sci ; 8(3): 218-23, 1994 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-7865481

RESUMEN

Previous studies from our laboratories have shown that UV-B irradiation at the site of an intradermal infection of herpes simplex virus (HSV) resulted in a higher incidence of zosteriform lesions and suppressed cellular immune responses to HSV in mice. In order to determine whether the production of T-cell-derived cytokine (IFN-gamma, IL-2 and IL-4) by immune cells from irradiated mice is also suppressed, we examined the production of cytokines by lymph node cells and spleen cells taken from UV-B irradiated, HSV type 1 (HSV-1)-infected mice. UV-B irradiation (120 mJ/cm2) prior to HSV-1 infection was found to markedly suppress IFN-gamma production compared to that of the non-irradiated control. IL-4 production was enhanced compared to IL-2 in the UV-B irradiated mice. These results suggest that alteration(s) in the cytokine production profile may therefore be involved in the development of severe skin lesions caused by HSV infection in UV-B irradiated mice.


Asunto(s)
Citocinas/biosíntesis , Herpes Simple/inmunología , Linfocitos/inmunología , Rayos Ultravioleta , Animales , Antígenos Virales/inmunología , Antígenos Virales/farmacología , Células Cultivadas , Citocinas/fisiología , Femenino , Herpes Simple/etiología , Herpes Simple/patología , Inmunidad Celular/efectos de la radiación , Interferón gamma/biosíntesis , Interleucina-2/biosíntesis , Interleucina-4/biosíntesis , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/efectos de la radiación , Activación de Linfocitos/efectos de la radiación , Linfocitos/patología , Linfocitos/efectos de la radiación , Ratones , Ratones Endogámicos BALB C , Simplexvirus/inmunología , Simplexvirus/fisiología , Bazo/citología , Bazo/inmunología , Bazo/efectos de la radiación
8.
Metabolism ; 49(11): 1395-9, 2000 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11092500

RESUMEN

We studied the effects of zenarestat, an aldose reductase inhibitor (ARI), on peripheral neuropathy in Zucker diabetic fatty (ZDF) rats, an animal model of type 2 diabetes. ZDF rats and their lean rats counterparts were fed a sucrose-containing diet, and zenarestat was given orally once a day for 8 weeks. Motor nerve conduction velocity (MNCV), F-wave minimal latency (FML), and sorbitol concentrations in the sciatic nerve were measured. In ZDF control rats, a remarkable accumulation of sorbitol, a delay in FML, and a slowing of MNCV were observed compared with lean rats. At a dose of 3.2 mg/kg, zenarestat had no significant effect on the delay in FML and the slowing of MNCV, although the sorbitol accumulation in the sciatic nerve was partially inhibited in ZDF rats. On the other hand, 32 mg/kg zenarestat treatment improved these nerve dysfunctions in ZDF rats, along with a reduction of nerve sorbitol accumulation almost to the level of lean rats. These data showed that zenarestat improved diabetic peripheral neuropathy in ZDF rats, a type 2 diabetes model, providing evidence for the therapeutic potential of zenarestat for the treatment of diabetic neuropathy.


Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Neuropatías Diabéticas/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Quinazolinas/uso terapéutico , Animales , Glucemia/análisis , Peso Corporal , Diabetes Mellitus Tipo 2/complicaciones , Neuropatías Diabéticas/complicaciones , Neuropatías Diabéticas/fisiopatología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Masculino , Quinazolinas/farmacología , Ratas , Ratas Zucker
9.
FEMS Microbiol Lett ; 203(2): 185-9, 2001 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-11583846

RESUMEN

We have constructed recombinant listeriolysin O (rLLO) and seeligeriolysin O (rLSO) from Listeria monocytogenes and Listeria seeligeri, respectively. In hemolysis and cholesterol-binding assays, the specific activity of recombinant toxin was lower for LSO as compared to LLO. To understand the molecular basis of this difference, in particular with respect to the conserved Trp-rich undecapeptide, a naturally occurring Ala to Phe substitution in LSO was introduced into rLLO. The rLLO:A488F hemolysin exhibited a reduced activity in both hemolysis and cholesterol-binding. The reverse mutation, inserted into rLSO, also increased the hemolytic activity of this mutant LSO. These results suggested that the natural replacement of Ala to Phe is involved in the weak cytolytic activity of LSO.


Asunto(s)
Toxinas Bacterianas , Colesterol/metabolismo , Proteínas de Choque Térmico , Proteínas Hemolisinas , Listeria , Alanina/química , Animales , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/toxicidad , Proteínas Hemolisinas/genética , Proteínas Hemolisinas/metabolismo , Proteínas Hemolisinas/toxicidad , Hemólisis , Listeria/metabolismo , Listeria monocytogenes/metabolismo , Mutación , Péptidos/química , Proteínas Recombinantes/metabolismo , Ovinos , Triptófano/química
10.
Cancer Chemother Pharmacol ; 42(1): 31-6, 1998.
Artículo en Inglés | MEDLINE | ID: mdl-9619755

RESUMEN

PURPOSE: FK973, a substituted dihydrobenzoxazine, is an antitumor antibiotic which has shown high therapeutic efficacy in a phase I study, but its development has been abandoned because of the side effect of vascular leak syndrome (VLS) in the clinical study. This study was performed to investigate whether or not FK317, a new benzmethoxy derivative of FK973, retains the antitumor activity of FK973 without the side effect of VLS. METHODS: VLS was evaluated by the volume of pleural effusion in rats. Cytotoxic activities were determined by a tetrazolium-based colorimetric assay (MTT assay) against murine (B16, P388) and human (HeLa S3, KB) tumor cell lines. Antitumor activities against murine ascitic leukemia (P388, L1210), murine solid tumors (reticulum cell sarcoma M5076, Colon 38 carcinoma) and human xenografts (mammary carcinoma MX-1, lung carcinoma LX-1) were examined. RESULTS: FK973 (1.8 mg/kg) given i.v. to rats induced pleural effusion, one of the elements of VLS, 36 days after the first dosing, but did not 28 days after dosing. This model reflects clinical VLS delayed-type effusion with high protein concentrations. In contrast, FK317 (1.0-3.2 mg/kg) did not induce pleural effusion at all. FK317 had stronger cytotoxic effects against in vitro cultured B16, P388, HeLa S3 and KB tumor cell lines, and in in vivo experiments, FK317 showed equivalent antitumor activity against P388, M5076 and MX-1, and more potent antitumor activity against L1210, Colon 38 and LX-1 compared with FK973. CONCLUSION: These results suggest that FK317 retains the antitumor activity of FK973 and does not induce VLS, and FK317 is a drug with high clinical potential for treating tumors in humans.


Asunto(s)
Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Síndrome de Fuga Capilar/inducido químicamente , Neoplasias Experimentales/tratamiento farmacológico , Oxazinas/efectos adversos , Oxazinas/farmacología , Animales , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Masculino , Ratones , Ratones Endogámicos , Mitomicina/efectos adversos , Mitomicina/farmacología , Derrame Pleural/inducido químicamente , Ratas , Ratas Sprague-Dawley , Células Tumorales Cultivadas
11.
Eur J Pharmacol ; 419(1): 99-105, 2001 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-11348636

RESUMEN

FK506 (Tacrolimus) is an effective immunosuppressant currently used worldwide in organ transplantation. Based on our recent findings that insulin-like growth factor-I (IGF-I) is important for the stimulation of choleresis in vivo, in this study we investigated the effect of FK506 on bile flow and the plasma and hepatic levels of IGF-I in rats. Intravenous treatment of rats with FK506 resulted in a significant increase in bile flow, whereas cyclosporin A induced a significant decrease. A significant increase in plasma levels of IGF-I was observed in rats 30 min after a single intravenous administration of FK506. Oral treatment of rats with FK506 for 1 week also resulted in an increase in both plasma and hepatic levels of IGF-I. Overall, this study showed that FK506 treatment increased bile flow and also induced an increase in the plasma and hepatic levels of IGF-I in rats, suggesting that a stimulation of hepatic IGF-I production by FK506 may contribute to its choleretic profile.


Asunto(s)
Bilis/metabolismo , Inmunosupresores/farmacología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Hígado/efectos de los fármacos , Tacrolimus/farmacología , Animales , Ciclosporina/farmacología , Hipofisectomía , Inmunosupresores/administración & dosificación , Factor I del Crecimiento Similar a la Insulina/química , Hígado/química , Hígado/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Tacrolimus/administración & dosificación
12.
Neurosci Lett ; 310(2-3): 81-4, 2001 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-11585572

RESUMEN

The effects of zenarestat, an aldose reductase inhibitor, on endoneurial blood flow (NBF) were explored in streptozotocin-induced diabetic rats. Rats were maintained on a diet of containing 0.09% zenarestat for 8 weeks, then NBF in the sciatic nerve was measured using microelectrode hydrogen polarography. NBF in the diabetic control rats was significantly lower than values in age-matched control rats, however, NBF was not significantly altered in diabetic rats treated with zenarestat. Direct application of nitric oxide synthase inhibitor, NG-nitro-L-arginine, did not affect NBF in diabetic control rats, whereas this application significantly reduced NBF both in age-matched control and zenarestat treated diabetic rats. Considerable levels of zenarestat were confirmed in the sciatic nerve in the drug treated rats. These data suggest that aldose reductase, such as zenarestat, might restore or prevent the alteration of endoneurial blood flow resulting from an impairment of nitric oxide function.


Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Neuropatías Diabéticas/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Nervios Periféricos/irrigación sanguínea , Quinazolinas/farmacología , Animales , Neuropatías Diabéticas/metabolismo , Hidrógeno/farmacocinética , Masculino , Microelectrodos , Óxido Nítrico/metabolismo , Nitroarginina/farmacología , Nervios Periféricos/enzimología , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional/efectos de los fármacos , Nervio Ciático/irrigación sanguínea , Nervio Ciático/enzimología
13.
Life Sci ; 68(12): 1439-48, 2001 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-11388695

RESUMEN

The effects of zenarestat, 3-(4-bromo-2-fluorobenzyl)-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazolineacetic acid, an aldose reductase inhibitor (ARI), on F-wave conduction abnormalities, nerve blood flow (NBF) reduction and sorbitol accumulation were studied in streptozotocin-induced diabetic rats. Two weeks after the induction of diabetes, zenarestat was given once a day for two weeks. In diabetic control rats, marked accumulation of sorbitol, reduction of NBF and prolongation of minimal F-wave latency (FWL) were observed as compared to normal rats. Zenarestat, at a dose of 32 mg/kg, inhibited sorbitol concentration to nearly the normal rat level and significantly improved not only NBF but also minimal FWL. At a dose of 3.2 mg/kg, sorbitol accumulation was inhibited by approximately 40% and there was a tendency to increase in NBF; however, minimal FWL was not improved at all. These data suggest that a highly inhibition of the nerve sorbitol accumulation is requisite for the treatment of diabetic peripheral neuropathy.


Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Diabetes Mellitus Experimental/metabolismo , Inhibidores Enzimáticos/farmacología , Conducción Nerviosa/efectos de los fármacos , Quinazolinas/farmacología , Tiempo de Reacción/efectos de los fármacos , Nervio Ciático/irrigación sanguínea , Animales , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Neuropatías Diabéticas/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Masculino , Conducción Nerviosa/fisiología , Quinazolinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Estreptozocina
14.
Anticancer Res ; 19(5B): 4099-103, 1999.
Artículo en Inglés | MEDLINE | ID: mdl-10628360

RESUMEN

Our recent study has demonstrated that B16 melanoma-induced cachexia in mice is inhibited by ponalrestat, an aldose reductase inhibitor, which has the ability to activate lipoprotein lipase (LPL) activity both in vitro and in vivo. In this study, the effect of bezafibrate and NO-1886, LPL activators, on B16 melanoma-induced cachectic symptoms was investigated in mice. Treatment with bezafibrate resulted in an attenuation of the decrease in the weight of epididymal fat and whole body lipid observed in mice following intraperitoneal inoculation of B16. The increase in the levels of triglyceride and non-esterified fatty acid, and a decrease in the level of glucose in the blood, which was induced by the presence of tumor, were also restored to that of normal mice after treatment with bezafibrate. The reduction in the weight of epididymal fat and whole body lipid induced by B16 was also ameliorated by NO-1886. Overall, this study demonstrated that cachexia induced by B16 melanoma in mice was alleviated by the LPL activators bezafibrate and NO-1886, suggesting the involvement of the impaired LPL activity in the establishment of cachexia syndrome in mice bearing B16 melanoma.


Asunto(s)
Benzamidas/farmacología , Bezafibrato/farmacología , Caquexia/tratamiento farmacológico , Activadores de Enzimas/farmacología , Hipolipemiantes/farmacología , Lipoproteína Lipasa/metabolismo , Melanoma Experimental/complicaciones , Compuestos Organofosforados/farmacología , Tejido Adiposo/metabolismo , Animales , Caquexia/etiología , Colesterol/metabolismo , Epidídimo/efectos de los fármacos , Ácidos Grasos no Esterificados/metabolismo , Glucosa/metabolismo , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Triglicéridos/metabolismo
15.
Anticancer Res ; 14(2A): 427-31, 1994.
Artículo en Inglés | MEDLINE | ID: mdl-8017842

RESUMEN

Insulin-like growth factor-I (IGF-I) is an important mitogen in breast cancer. We studied here the effects of a new antiestrogen drug, droloxifene (DROL, (E)-alpha-[p-[2-(dimethylamino) ethoxy]-phenyl]-alpha'-ethyl-3-stilbenol) and tamoxifen (TAM) on the IGF-I-stimulated growth of estrogen receptor (ER) positive breast cancer cells, MCF-7 and their mechanism of action. IGF-I secretion from MCF-7 was increased by the addition of estrogen. Externally added IGF-I stimulated the growth of MCF-7 but not ER negative breast cancer cells, MDA-MB-231. DROL and TAM inhibited the IGF-I-stimulated growth of MCF-7. A 2 hr treatment with both drugs did not block IGF-I binding to the receptors in MCF-7. However, a 4 day treatment with DROL decreased the number of IGF-I receptors without altering the binding affinity in MCF-7. These results suggest that DROL can exert its antitumor activity against ER positive breast cancer not only by blocking the E2 binding to the ER, but also by counteracting the mitogenic effect of IGF-I.


Asunto(s)
Antineoplásicos/toxicidad , División Celular/efectos de los fármacos , Antagonistas de Estrógenos/toxicidad , Factor I del Crecimiento Similar a la Insulina/farmacología , Tamoxifeno/análogos & derivados , Neoplasias de la Mama , Línea Celular , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Cinética , Receptor IGF Tipo 1/metabolismo , Receptores de Estrógenos/fisiología , Tamoxifeno/toxicidad , Células Tumorales Cultivadas
16.
Anticancer Res ; 19(1A): 341-8, 1999.
Artículo en Inglés | MEDLINE | ID: mdl-10226565

RESUMEN

Lipoprotein lipase (LPL) is a key regulatory enzyme responsible for the hydrolysis of triglyceride (TG)-rich lipoproteins. The reduction in LPL activity is observed in tumor bearing animals and cancer patients with cachectic symptoms, suggesting an involvement of LPL in inducing cancer cachexia. During a screening program for anti-cachectic agents we found that ponalrestat, an aldose reductase inhibitor, activates LPL activity. Ponalrestat increased the activity of LPL in adipose tissue in mice. The effect of ponalrestat on B16 melanoma-induced cachectic symptoms was next investigated in mice. The decrease in the weight of epididymal fat, carcass and whole body lipid was observed in mice following intraperitoneal inoculation of B16, compared to mice without the tumor inoculation. Treatment with ponalrestat resulted in the attenuation of the decrease in the tissue weight. The increase in the levels of TG and non-esterified fatty acid, and a decrease in the level of glucose in the blood, which was induced by the presence of tumor, were also restored to those of normal mice following ponalrestat treatment. The reduction in locomotor activity in tumor bearing mice was partially restored by the treatment with ponalrestat. Overall, this study demonstrated that ponalrestat, an aldose reductase inhibitor, possesses potent LPL activating activity and that the cachexia induced by B16 melanoma was alleviated by treatment with 'ponalrestat, suggesting that ponalrestat, a LPL activating agent, has a therapeutic potential for the treatment of cancer cachexia.


Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Caquexia/prevención & control , Inhibidores Enzimáticos/farmacología , Lipoproteína Lipasa/metabolismo , Melanoma Experimental/complicaciones , Ftalazinas/farmacología , Células 3T3 , Animales , Activación Enzimática/efectos de los fármacos , Femenino , Lípidos/análisis , Masculino , Melanoma Experimental/metabolismo , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Conejos
17.
Anticancer Res ; 19(5B): 4091-7, 1999.
Artículo en Inglés | MEDLINE | ID: mdl-10628359

RESUMEN

Our recent study has demonstrated that ponalrestat, an aldose reductase inhibitor, activates lipoprotein lipase (LPL) activity in the adipose tissue and alleviates the cachectic symptoms induced by B16 melanoma in mice. In this study, the effect of ponalrestat on cachexia symptoms in nude mice bearing human melanomas G361 and SEKI was investigated because it has been suggested that the suppression of LPL has an important role in cachexia induction by these two melanomas in nude mice. Mice bearing G361 subcutaneously did not gain weight and became cachectic, associated with the tumor growth. Tumor growth was not affected by ponalrestat, nevertheless treatment with ponalrestat resulted in an amelioration of the reduction in the weight of body mass, epididymal fat, gastrocnemius muscle, carcass and whole body lipid induced by the presence of G361. A severe weight loss observed in nude mice bearing SEKI was also partially attenuated by ponalrestat treatment. Overall, this study showed that ponalrestat is effective in the attenuation of the cachectic symptoms induced by human melanomas G361 and SEKI in nude mice, suggesting that ponalrestat has a potential usefulness for the treatment of cancer cachexia.


Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Caquexia/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Interleucina-6 , Melanoma/complicaciones , Ftalazinas/farmacología , Animales , Peso Corporal/efectos de los fármacos , Caquexia/enzimología , Caquexia/etiología , Ingestión de Alimentos/efectos de los fármacos , Inhibidores Enzimáticos/química , Epidídimo/efectos de los fármacos , Inhibidores de Crecimiento/biosíntesis , Humanos , Factor Inhibidor de Leucemia , Linfocinas/biosíntesis , Masculino , Melanoma/enzimología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Músculo Esquelético/efectos de los fármacos , Trasplante de Neoplasias , Ftalazinas/química , Factores de Tiempo
18.
Anticancer Res ; 20(5A): 3111-6, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-11062730

RESUMEN

Several lines of evidence have postulated that reduction in the activity of lipoprotein lipase (LPL) is involved in cachexia induction in cancer patients. Recently we have demonstrated that murine melanoma B16 has the ability to reduce the LPL activity and thereby induce cachexia symptoms in mice following intraperitoneal inoculation. In order to further investigate the relationship between LPL activity and cachectic syndrome, cachexia models other than melanoma B16 are required. However, there are few animal cachexia models in which LPL activity is involved in the induction of cachectic symptoms. In this study, cachectic symptoms and plasma LPL activity were investigated in mice bearing EL-4 mouse lymphoma. In EL-4 bearing mice the body weight including tumor weight in the abdominal cavity was rather higher than that of normal mice without tumor, whereas weights of carcass wet and gastrocnemius muscle were significantly decreased in EL-4 bearing mice. Elevated blood levels of triglyceride and non-esterified fatty acid were observed in mice bearing EL-4, associated with the impaired plasma LPL activity. Overall, this study indicated that EL-4 lymphoma in mice results in a severe cachexia which is possibly related to impaired LPL activity and also provided a useful cachexia model for understanding the role of LPL in the development of cancer cachexia.


Asunto(s)
Caquexia/enzimología , Lipoproteína Lipasa/metabolismo , Linfoma/enzimología , Animales , Caquexia/complicaciones , Caquexia/fisiopatología , Linfoma/complicaciones , Linfoma/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Células Tumorales Cultivadas
19.
Anticancer Res ; 17(3C): 1919-23, 1997.
Artículo en Inglés | MEDLINE | ID: mdl-9216645

RESUMEN

BACKGROUND: A calpain inhibitor, calpeptin, inhibited the cell growth of ER (estrogen receptor) positive breast cancer cells, such as MCF-7, T-47D, and ZR-75-1 in the presence of E2. The mechanism of this inhibition has not been clarified yet. MATERIALS AND METHODS: MCF-7 cells were employed to investigate the mechanism of the inhibition. We studied the effect of calpeptin on the secretion of insulin-like growth factor-I (IGF-I) and transforming growth factor (TGF-alpha). RESULTS: The secretion of IGF-I or TGF-alpha was not changed by calpeptin either in the presence or absence of E2. Moreover, the binding of IGF-I or TGF-alpha to MCF-7 cells augmented by the addition of E2 was not affected by calpeptin. CONCLUSIONS: These results indicated that the inhibition of cell growth in MCF-7 by calpeptin was not due to the modulation of autocrine growth factors and their receptors.


Asunto(s)
Calpaína/antagonistas & inhibidores , Dipéptidos/farmacología , Estradiol/farmacología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor de Crecimiento Transformador alfa/metabolismo , Neoplasias de la Mama , División Celular/efectos de los fármacos , Inhibidores de Cisteína Proteinasa/farmacología , Receptores ErbB/efectos de los fármacos , Receptores ErbB/metabolismo , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/biosíntesis , Cinética , Receptor IGF Tipo 1/efectos de los fármacos , Receptor IGF Tipo 1/metabolismo , Receptores de Estrógenos/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/efectos de los fármacos , Receptores de Progesterona/metabolismo , Factor de Crecimiento Transformador alfa/biosíntesis , Células Tumorales Cultivadas
20.
Anticancer Res ; 18(1A): 139-44, 1998.
Artículo en Inglés | MEDLINE | ID: mdl-9568068

RESUMEN

Cancer cachexia, characterized by weight loss and progressive tissue wasting, has been postulated to be mediated by cytokines. In this study the effect of FR143430, (2-(4-fluorophenyl)-4, 5, 6, 7-tetrahydro-3-(4-pyridyl)pyrazolo[1, 5-a]pyrimidine monohydrochloride), an inhibitor of Interleukin-1 and Tumor necrosis factor-a (TNF- a), on adenocarcinoma colon26-induced cachexia was investigated in mice. Tumor growth was not affected. Nevertheless, treatment with FR143430 (0.1 to lmg) into the tumor resulted in the attenuation of the reduction in body weight, food intake, epididymal fat and carcass weight, the decrease in the circulating levels of triglyceride and glucose, and the increase in the circulating levels of total cholesterol, non esterified free fatty acid (NEFA) and total protein, which were induced by the presence of the tumor. However, oral treatment with FR143430 failed to show an inhibitory effect on cachexia induction. Overall, this study demonstrated that the cachexia induced by colon26 was alleviated by the injection of FR143430 into the tumor in sufficient quantity, without any effect on tumor growth, suggesting the potential utility of cytokine suppressive agents e for the treatment of cancer cachexia.


Asunto(s)
Caquexia/tratamiento farmacológico , Citocinas/antagonistas & inhibidores , Neoplasias Experimentales/tratamiento farmacológico , Pirazoles/farmacología , Pirimidinas/farmacología , Animales , Caquexia/sangre , Células Cultivadas , Neoplasias del Colon/sangre , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Humanos , Leucocitos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Monocitos/efectos de los fármacos , Neoplasias Experimentales/sangre , Neoplasias Experimentales/patología
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